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Bcl-2 is a highly significant prognostic marker of hormone-receptor-positive, human epidermal growth factor receptor-2-negative breast cancer

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Abstract

B‐cell lymphoma‐2 (Bcl‐2) is one of the most important anti‐apoptotic genes. Although Bcl-2 promotes tumor cell survival in vitro, previous studies have shown conflicting results regarding the association between Bcl-2 and breast cancer survival. The aim of this study was to assess the prognostic significance of Bcl-2 according to the molecular tumor subtype in primary invasive breast cancer patients. The relationship between immunohistochemical Bcl-2 expression and overall survival was analyzed in 2399 primary invasive breast cancer patients treated by curative surgery. Patients were classified into four subtypes based on hormone receptor (HR) and human epidermal growth factor receptor‐2 (HER2) status: HR+/HER2−, HR+/HER2+, HR−/HER2+, and HR−/HER2−. A total of 1304 patients (54.4 %) had Bcl‐2 positive (+) tumors by immunohistochemistry. Bcl‐2 (+) tumors were significantly associated with a younger age (<50 years), early stage, lower grade, positive expression of HR, and negative expression of HER2. In the HR+/HER2− group, patients with Bcl‐2 (+) tumors showed a significantly better prognosis (p < 0.001). In contrast, there was no significant prognostic effect of Bcl‐2 expression in other subtypes. In multivariate analysis, Bcl‐2 positivity remained an independent, favorable prognostic factor in the HR+/HER2− subtype (hazard ratio, 0.609; 95 % confidence interval, 0.424–0.874; p < 0.007). The prognostic significance of Bcl‐2 expression differed according to the molecular subtype of breast cancer. The expression of Bcl‐2 was an independent, favorable prognostic factor in breast cancer patients with the HR+/HER2− subtype.

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References

  1. Carter CL, Allen C, Henson DE (1989) Relation of tumor size, lymph node status, and survival in 24,740 breast cancer cases. Cancer 63:181–187. doi:10.1001/jama.1964.03060170107050

    Article  CAS  PubMed  Google Scholar 

  2. Nemoto T, Vana J, Bedwani RN, Baker HW, McGregor FH, Murphy GP (1980) Management and survival of female breast cancer: results of a national survey by the American College of Surgeons. Cancer 45:2917–2924. doi:10.1002/1097-0142(19800615)45:12<2917:aid-cncr2820451203>3.0.co;2-m

    Article  CAS  PubMed  Google Scholar 

  3. Ross JS, Fletcher JA, Linette GP, Stec J, Clark E, Ayers M, Symmans WF, Pusztai L, Bloom KJ (2003) The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy. Oncologist 8:307–325. doi:10.1634/theoncologist.8-4-307

    Article  CAS  PubMed  Google Scholar 

  4. Scholzen T, Gerdes J (2000) The Ki-67 protein: from the known and the unknown. J Cell Physiol 182:311–322. doi:10.1002/(sici)1097-4652(200003)182:3<311:aid-jcp1>3.0.co;2-9

    Article  CAS  PubMed  Google Scholar 

  5. van’t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–536. doi:10.1038/415530a

    Article  Google Scholar 

  6. Sparano JA, Paik S (2008) Development of the 21-gene assay and its application in clinical practice and clinical trials. J Clin Oncol 26:721–728. doi:10.1200/jco.2007.15.1068

    Article  PubMed  Google Scholar 

  7. Cardoso F, Van’t Veer L, Rutgers E, Loi S, Mook S, Piccart-Gebhart MJ (2008) Clinical application of the 70-gene profile: the MINDACT trial. J Clin Oncol 26:729–735. doi:10.1200/jco.2007.14.3222

    Article  PubMed  Google Scholar 

  8. Adams JM, Cory S (1998) The Bcl-2 protein family: arbiters of cell survival. Science 281:1322–1326. doi:10.1126/science.281.5381.1322

    Article  CAS  PubMed  Google Scholar 

  9. Cory S, Huang DC, Adams JM (2003) The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene 22:8590–8607. doi:10.1038/sj.onc.1207102

    Article  CAS  PubMed  Google Scholar 

  10. Tzifi F, Economopoulou C, Gourgiotis D, Ardavanis A, Papageorgiou S, Scorilas A (2012) The role of Bcl2 family of apoptosis regulator proteins in acute and chronic leukemias. Adv Hematol 2012:524308. doi:10.1155/2012/524308

    PubMed Central  PubMed  Google Scholar 

  11. Hellemans P, van Dam PA, Weyler J, van Oosterom AT, Buytaert P, Van Marck E (1995) Prognostic value of bcl-2 expression in invasive breast cancer. Br J Cancer 72:354–360. doi:10.1038/bjc.1995.338

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Callagy GM, Pharoah PD, Pinder SE, Hsu FD, Nielsen TO, Ragaz J, Ellis IO, Huntsman D, Caldas C (2006) Bcl-2 is a prognostic marker in breast cancer independently of the Nottingham prognostic index. Clin Cancer Res 12:2468–2475. doi:10.1158/1078-0432.ccr-05-2719

    Article  CAS  PubMed  Google Scholar 

  13. Dawson SJ, Makretsov N, Blows FM, Driver KE, Provenzano E, Le Quesne J, Baglietto L, Severi G, Giles GG, McLean CA, Callagy G, Green AR, Ellis I, Gelmon K, Turashvili G, Leung S, Aparicio S, Huntsman D, Caldas C, Pharoah P (2010) BCL2 in breast cancer: a favourable prognostic marker across molecular subtypes and independent of adjuvant therapy. Br J Cancer 103:668–675. doi:10.1038/sj.bjc.6605736

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Silvestrini R, Veneroni S, Daidone MG, Benini E, Boracchi P, Mezzetti M, Di Fronzo G, Rilke F, Veronesi U (1994) The Bcl-2 protein: a prognostic indicator strongly related to p53 protein in lymph node-negative breast cancer patients. J Natl Cancer 86:499–504. doi:10.1093/jnci/86.7.499

    Article  CAS  Google Scholar 

  15. Lipponen P, Pietilainen T, Kosma VM, Aaltomaa S, Eskelinen M, Syrjanen K (1995) Apoptosis suppressing protein bcl-2 is expressed in well-differentiated breast carcinomas with favourable prognosis. J Pathol 177:49–55. doi:10.1002/path.1711770109

    Article  CAS  PubMed  Google Scholar 

  16. Yu B, Sun X, Shen HY, Gao F, Fan YM, Sun ZJ (2010) Expression of the apoptosis-related genes Bcl-2 and BAD in human breast carcinoma and their associated relationship with chemosensitivity. J Exp Clin Cancer Res 29:1–7. doi:10.1186/1756-9966-29-107

    Article  Google Scholar 

  17. Yang Q, Moran MS, Haffty BG (2009) Bcl-2 expression predicts local relapse for early stage breast cancer receiving conserving surgery and radiotherapy. Breast Cancer Res Treat 115:343–348. doi:10.1007/s10549-008-0068-4

    Article  CAS  PubMed  Google Scholar 

  18. Martinez-Arribas F, Alvarez T, Del Val G, Martin-Garabato E, Nunez-Villar MJ, Lucas R, Sánchez J, Tejerina A, Schneider J (2007) Bcl-2 expression in breast cancer: a comparative study at the mRNA and protein level. Anticancer Res 27:219–222

    CAS  PubMed  Google Scholar 

  19. Amundson SA, Myers TG, Scudiero D, Kitada S, Reed JC, Fornace AJ Jr (2000) An informatics approach identifying markers of chemosensitivity in human cancer cell lines. Cancer Res 60:6101–6110

    CAS  PubMed  Google Scholar 

  20. Kang MH, Reynolds CP (2009) Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res 15:1126–1132. doi:10.1158/1078-0432.CCR-08-0144

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. O’Brien S, Moore JO, Boyd TE et al (2009) 5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen. J Clin Oncol 27:5208–5212. doi:10.1200/JCO.2009.22.5748

    Article  PubMed  Google Scholar 

  22. Pezzella F, Turley H, Kuzu I, Tungekar MF, Dunnill MS, Pierce CB, Harris A, Gatter KC, Mason DY (1993) Bcl-2 protein in non-small-cell lung cancer. N Engl J Med 329:690–694. doi:10.1056/NEJM199309023291003

    Article  CAS  PubMed  Google Scholar 

  23. Manne U, Myers RB, Moron C, Poczatek RB, Dillard S, Weiss H, Brown D, Srivastava S, Grizzle WE (1997) Prognostic significance of Bcl-2 expression and p53 nuclear accumulation in colorectal adenocarcinoma. Int J Cancer 74:346–358. doi:10.1002/(SICI)1097-0215(19970620)74:3<346::AID-IJC19>3.0.CO;2-9

  24. Del Bufalo D, Biroccio A, Leonetti C, Zupi G (1997) Bcl-2 overexpression enhances the metastatic potential of a human breast cancer line. FASEB J 11:947–953

    PubMed  Google Scholar 

  25. DiVito KA, Berger AJ, Camp RL, Dolled-Filhart M, Rimm DL, Kluger HM (2004) Automated quantitative analysis of tissue microarrays reveals an association between high Bcl-2 expression and improved outcome in melanoma. Cancer Res 64:8773–8777. doi:10.1158/0008-5472.CAN-04-1387

    Article  CAS  PubMed  Google Scholar 

  26. Knowlton K, Mancini M, Creason S, Morales C, Hockenberry D, Anderson BO (1998) Bcl-2 slows in vitro breast cancer growth despite its antiapoptotic effect. J Surg Res 76:22–26. doi:10.1006/jsre.1998.5277

    Article  CAS  PubMed  Google Scholar 

  27. Pietenpol JA, Papadopoulos N, Markowitz S, Willson JK, Kinzler KW, Vogelstein B (1994) Paradoxicial inhibition of solid tumor cell growth by bcl2. Cancer Res 54:3714–3717

    CAS  PubMed  Google Scholar 

  28. Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lønning PE, Børresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406:747–752. doi:10.1038/35021093

    Article  CAS  PubMed  Google Scholar 

  29. Cuzick J, Dowsett M, Pineda S, Wale C, Salter J, Quinn E, Zabaglo L, Mallon E, Green AR, Ellis IO, Howell A, Buzdar AU, Forbes JF (2011) Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the Genomic Health recurrence score in early breast cancer. J Clin Oncol 29:4273–4278. doi:10.1200/JCO.2010.31.2835

    Article  PubMed  Google Scholar 

  30. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S, Deming SL, Geradts J, Cheang MC, Nielsen TO, Moorman PG, Earp HS, Millikan RC (2006) Race, breast cancer subtypes, and survival in the Carolina breast cancer study. JAMA 295:2492–2502. doi:10.1001/jama.295.21.2492

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This research was supported by grants from the Radiological Translational Research Program (50451-2013).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

This study complies with the current laws of South Korea inclusive ethics approval.

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    Authors and Affiliations

    1. Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 215‐4 Gongneung‐dong, Nowon‐ku, Seoul, 139‐706, Republic of Korea

      Min-Ki Seong, Jangmoo Byeon, Yeun-Ju Sohn, Hyun-Ah Kim & Woo Chul Noh

    2. Department of Pathology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea

      Hyesil Seol

    3. Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea

      Jin-Kyung Lee

    4. Department of Surgery, Breast Care Center, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Gyeonggi-do, Republic of Korea

      Eun-Kyu Kim

    5. Uva Surgery, Busan, Republic of Korea

      Ju-Young Lee

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    1. Min-Ki Seong
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    Correspondence to Woo Chul Noh.

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    Min-Ki Seong and Ju-Young Lee have contributed equally to this study.

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    Seong, MK., Lee, JY., Byeon, J. et al. Bcl-2 is a highly significant prognostic marker of hormone-receptor-positive, human epidermal growth factor receptor-2-negative breast cancer. Breast Cancer Res Treat 150, 141–148 (2015). https://doi.org/10.1007/s10549-015-3305-7

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    • DOI: https://doi.org/10.1007/s10549-015-3305-7

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